ABSTRACT Alzheimer?s disease (AD) results in a progressive degeneration of neural circuits in the brain. The long-term goals of our research are to understand how the neural circuit alterations that accompany AD result in the concomitant decline in cognitive and mental abilities. The primary objective of this proposal is to characterize age-related alterations to the layer 5 corticothalamic versus layer 2/3 corticocortical projections in transgenic mouse models of AD. The layer 5 corticothalamic pathway supports an important, yet largely neglected, route for information flow in the forebrain that is critical for normal cognitive processes. The central hypothesis is that the layer 5 corticothalamic pathway is altered later than the layer 2/3 corticocortical pathways during the progression of AD. This is expected to result in changes to functional connectivity in the forebrain and underlie the progression of cognitive deficits associated with the disease. Several neuroanatomical and neurophysiological features of these pathways have been identified, which forms the basis for the proposed investigation. The specific aims of this project are to characterize the alterations to the layer 5 corticothalamic versus layer 2/3 corticocortical pathways with age in mouse models of AD by examining: 1) changes to the neuroanatomical connections of the layer 5 and layer 2/3 neurons and 2) alterations to neurophysiological responses in higher-order thalamic nuclei and cortical areas mediated by activation of pathways from these layers. The proposed experiments are expected to identify the age-related changes to forebrain functional connectivity mediated by these different pathways and guide our future investigations aimed at directly linking alterations to these pathways with the cognitive deficits experienced during AD and ultimately restoring normal behavior in this model system. These experiments will have a positive impact by illuminating the potentially important role of the layer 5 corticothalamic pathways in AD, which will lead to enhanced diagnostics and prospective treatments for this conditions and other neurodegenerative disorders.